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ASCO 2021 | EV-103: enfortumab vedotin and pembrolizumab in urothelial carcinoma

Terence W. Friedlander, MD, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, provides updates on the multicohort Phase Ib/II EV-103 trial (NCT03288545) of enfortumab vedotin and pembrolizumab in first-line locally advanced or metastatic urothelial carcinoma. In a cohort of 45 patients who were cisplatin-ineligible, 93% of patients showed tumor shrinkage with an overall response rate (ORR) was 73.3%. Dr Friedlander additionally discusses the safety profile of enfortumab vedotin and pembrolizumab treatment as well as PD-L1 as a biomarker in urothelial cancer. This interview took place at the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting.

Transcript (edited for clarity)

EV-103 study, I think, is a pretty exciting study. And I’m really honored to be able to present the data at the ASCO Annual Meeting this year.

So, it’s a multi-armed study that is looking at the combination of enfortumab vedotin. This is an antibody-drug conjugate directed against Nectin-4. The drug itself is MMAE, monomethyl auristatin E, which is a type of chemotherapy. And it’s being given to patients with urothelial cancer or really metastatic, conventionally called, bladder cancer...

EV-103 study, I think, is a pretty exciting study. And I’m really honored to be able to present the data at the ASCO Annual Meeting this year.

So, it’s a multi-armed study that is looking at the combination of enfortumab vedotin. This is an antibody-drug conjugate directed against Nectin-4. The drug itself is MMAE, monomethyl auristatin E, which is a type of chemotherapy. And it’s being given to patients with urothelial cancer or really metastatic, conventionally called, bladder cancer.

So, enfortumab vedotin has been developed as a monotherapy by itself in a number of different trials. The most recent phase three trial just reported the EV-301 study, which showed that, as a single agent in patients who’ve already had chemotherapy and have already had immune therapy, that enfortumab vedotin by itself, has a fair amount of activity with almost about 50% response rate in a very heavily pretreated patient population.

And so, that’s exciting data because it’s now FDA approved in the United States, I think, since 2019, to treat very advanced metastatic urothelial cancer. Because the drug is so active by itself, investigators, my colleagues and I talked with the company that makes the Seattle Genetics, now called Seagen, about doing a study where we combine enfortumab vedotin with other therapies that are either already approved or in development for urothelial cancer. And the most, I think, interesting one of those, at least in my take, was to combine it with immune therapy. PD-1 immune therapy, specifically, a drug called pembrolizumab.

And so, the study started out with a dose-escalation where we’re combining enfortumab vedotin and pembrolizumab together, and then into a dose expansion cohort to see what the activity was. And instead of giving it late in the course of therapy, after cancers become resistant to chemo, or the cancers become resistant to immune therapy, this study is looking in treatment-naive patients.

So, patients who’ve never had systemic therapy for metastatic urothelial cancer, and specifically in a patient population that is not eligible for cisplatin-based chemotherapy. Cisplatin is this standard of care chemotherapy. As of now, as of 2021, when patients are ineligible for cisplatin chemotherapy, often, they’re offered carboplatin chemotherapy, but the outcomes are not as good for those patients.

So, the study really focuses on this metastatic cisplatin-ineligible urothelial cancer population, and is investigating this combination of both enfortumab vedotin and other partners.

In the poster we’re presenting now at ASCO, we’re presenting the Cohort A, which was the first cohort, which looks at the combination of EV and pembrolizumab together. Both with the five patients who were included in the dose escalation and then the 40 patients were included in dose expansion. And we have just about two years of follow-up. In fact, a little over two years of follow-up for all these patients as a median follow-up.

And so, some of this data has been presented before in ESMO meeting and at previous ASCO meetings, but this is the longest term follow-up we have to-date for this study.

So, the study itself, as I mentioned, is looking at the first 45 patients included in the trials. When we look at the baseline characteristics, it’s pretty representative of metastatic urothelial cisplatin-ineligible population. About 80% of the patients who enrolled were men. The average age was just under 70 years old. Most of the patients were [ECOG zero or one 00:04:04], over 80% of the patients. The majority had cancer of the bladder as opposed to the upper tract, although, we did have 33% of patients had disease in the ureters and the renal pelvis. Most patients had visceral metastatic disease. 84% of the patients had disease in an organ, and 31% of all the patients had liver metastatic disease. And that’s important because patients who have cancer metastatic to the liver have a much worse prognosis.

So, especially, cisplatin-ineligible patients with metastatic disease in the liver have a really unfortunately poor outcomes compared to other patients. Now, there was a fair display of whether patients were PD-L1 positive or negative, or whether just… We didn’t have the data on that. It was just about even between those three groups.

Perhaps, the most exciting data was looking at the response rates. So, what we saw were that 93% of patients had some shrinkage of tumors from their initial scans, from their baseline scans. Of the total, 73% had confirmed responses by resist criteria. And just to put that in context, the most recent phase three trials, that reported in this, is basically similar patient population. This is the KEYNOTE 361 study and the IMvigor 130 study. The overall response rates to chemotherapy plus PD-1 therapy, and those trials were on the order of 40 to 50%.

The highest response rate was 54% in the KEYNOTE study. This is 73%, so that’s significantly higher. And while it’s a smaller study, it’s only 45 patients, it’s not hundreds of patients, it’s still quite encouraging and quite exciting to see the majority of patients, almost the vast majority of patients having some response to this regimen.

I think the other important piece here is that it’s a regimen that doesn’t include traditional chemotherapy. There’s no platinum involved here. And while platinum has activity and can be effective against urothelial cancer, it also carries a lot of side effects. Toxicity, neuropathy, mild suppression, and risks for organ damage to the kidneys and nerves. And so, avoiding platinum is, I think, a fairly worthy goal for a lot of these patients.

Looking at the responses, the response happened in patients who are PD-L1 positive, as well as PD-L1 negative, and I think that’s quite important as well. It implies that you don’t need to screen people for PD-L1 status in order to give them this combination, assuming this data holds up in larger studies.

And they didn’t screen patients for Nectin-4, which was the target of enfortumab. And that’s because earlier studies have shown that 80 to 90% of urothelial cancers have high levels of Nectin-4 expression. And we didn’t want to exclude people based on the fact that most patients were going to be positive regardless. When patients responded, they responded early, so the average time, the median time to the first response, was only two months. So, you can give this therapy and see, at least in this study, when we gave the therapy, we saw that people were responding fairly quickly. That’s somewhat reassuring that we don’t have to wait a long time to see responses.

And then when we look at the longer-term outcomes, once a patient’s responding, the median duration of response was 25 months. So, that’s over two years of responding. And that’s basically unprecedented for urothelial cancer to see patients start responding and they continue to respond for two years.

To really put this in context, if you jump back 10 years ago, there was a phase three trial of carboplatin and gemcitabine. And the overall survival in that study, the median time that patients lived, was only nine months. And here, we have a study that’s showing just remarkably a lot better outcomes. The overall survival in this study, with the median follow-up of just over two years, is 26 months. You compare that back to nine months, which is what we had about 10 years ago. So, this is really… Again, it’s a phase two study, so it’s… I don’t want to overemphasize the data, but this is pretty exciting. And when we do phase one, phase two trials, this is really what we’re looking for as a signal. And I think this is a fairly robust signal.

To finish up, the toxicity of the regimen is pretty similar to what we’ve observed before when the study was presented previously. Overall, it seems to be fairly well-tolerated. Most patients had some side effects. I think peripheral sensory neuropathy, was, perhaps, the most common, and that’s an on-target effect of the MMAE chemotherapy. Skin issues, rashes and pruritis and other skin problems was also fairly common. So, we saw about 66% of patients had any skin reaction. Of them, there were [inaudible 00:09:12] total, about 20% had grade three reactions, almost all of those were addressable and treatable. 90% of them got better with treatment.

The sensory neuropathy occurred almost at a similar frequency. Fortunately, that severe sensory neuropathy was only about 4% of patients that was harder to fix. Certainly, dose reductions can help or dose holds. So, that’s about two-thirds of patients had improvement in neuropathy, but it’s a certainly consideration with this regimen. And the rest of the side effects are listed in the poster. I think the other important piece of the… When we look at the toxicity data, the adverse event data is that we didn’t see immune-related adverse events at a higher frequency than what we’ve seen previously with pembrolizumab studies. So, it doesn’t appear at least in this cohort that adding enfortumab vedotin to pembrolizumab increases the number of immune-related adverse events.

So, putting it all together, I think this is a pretty remarkable findings, in a sense, that we’re having the majority of patients are responding to this regimen. It’s platinum-free, it’s in a patient population that, historically, has had poor outcomes, with being cisplatin-ineligible, as well as having a fair amount of patients with liver metastatic disease. For the first time ever, we’re reporting the median overall survival, which is 26 months, which, I think, is unprecedented in this group. Again, it’s a phase one, phase two study. So, we need more patients. We need larger cohorts to really confirm this.

As the last piece of the… Well, this data is focused on Cohort A, which is the combination of enfortumab and pembrolizumab. There is a Cohort K to this trial that’s also accruing. And that’s a randomized cohort where patients are randomized. Basically, the same entry criteria, but randomized to getting either enfortumab alone or enfortumab plus pembrolizumab, which is the regimen that we just talked about.

And that’s going to try and evaluate the relative contribution of the EV versus the EV plus pembro. And if that’s positive, that may be enough to seek regulatory approval for the combination. And so, I think putting it all together, again, it’s a big honor for me to be able to present this data. I think it’s quite exciting.

The PD-L1 biomarker in urothelial cancer is very complex. It’s not a one-to-one where, if somebody is PD-L1 positive, they definitely respond to immune therapy, and if they’re PD-L1 negative, they don’t. And if you look across about five different clinical trials, they’re five different results. For example, in the KEYNOTE-045 study, it didn’t matter. This is a second-line study of pembrolizumab. It didn’t matter what the PD-L1 status was. The response rates were almost identical, whereas in the KEYNOTE-052 study, it did seem to matter. And they’re same drug, almost the same patient population, or at least a similar patient population.

So, I’m not sure what the future holds for PD-L1 testing in urothelial cancer. I don’t screen people with very limited exceptions. I don’t screen people and decide on PD-L1 therapy based just on the PD-L1 results, but I’ve seen the evolution. And I think it’s important to look for this, as we do these trials, to try and be clear about what’s going on.

There is… I alighted it over it at the beginning, but there is a rationale beyond just saying we have two active drugs, pembrolizumab and EV in urothelial cancer. There’s some preclinical evidence that, when cancer cells are treated with EV, and with this MMAE, that when they die, the immune system is involved. There’s immunogenic cell death. So, it involves the immune system coming in, and either killing the cancer cells or helping to identify cancer cells and kill them. And so the thought is that, maybe there’s synergy by adding EV to pembro. With the idea that it’s not just one plus one equals two, but maybe, one plus one equals three. And it’s not something proven by any means. I don’t claim that, that’s what’s happening here, but that’s the hope that we’re generating a waking-up-the-immune-system, if you will, to recognize the cancer.

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Disclosures

Terence W. Friedlander, MD has received research funding from Seagen related to the conduct of this trial, as well as consulting for Merck and EMD Serono.